SMAD4 feedback regulates the canonical TGF-β signaling pathway to control granulosa cell apoptosis

被引：71

作者：

Du, Xing ^{[1
]}

Pan, Zengxiang ^{[1
]}

Li, Qiqi ^{[1
]}

Liu, Honglin ^{[1
]}

Li, Qifa ^{[1
]}

机构：

[1] Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing 210095, Jiangsu, Peoples R China

来源：

CELL DEATH & DISEASE | 2018年 / 9卷

基金：

中国国家自然科学基金;

关键词：

GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR; EXPRESSION;

D O I：

10.1038/s41419-017-0205-2

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Canonical TGF-beta signals are transduced from the cell surface to the cytoplasm, and then translocated into the nucleus, a process that involves ligands (TGF-beta 1), receptors (TGFBR2/1), receptor-activated SMADs (SMAD2/3), and the common SMAD (SMAD4). Here we provide evidence that SMAD4, a core component of the canonical TGF-beta signaling pathway, regulates the canonical TGF-beta signaling pathway in porcine granulosa cells (GCs) through a feedback mechanism. Genome-wide analysis and qRT-PCR revealed that SMAD4 affected miRNA biogenesis in GCs. Interestingly, TGFBR2, the type II receptor of the canonical TGF-beta signaling pathway, was downregulated in SMAD4-silenced GCs and found to be a common target of SMAD4-inhibited miRNAs. miR-425, the most significantly elevated miRNA in SMAD4-silenced GCs, mediated the SMAD4 feedback regulation of the TGF-beta signaling pathway. This was accomplished through a direct interaction between the transcription factor SMAD4 and the miR-425 promoter, and a direct interaction between miR-425 and the TGFBR2 3'-UTR. Furthermore, miR-425 enhanced GC apoptosis by targeting TGFBR2 and the canonical TGF-beta signaling pathway, which was rescued by SMAD4 and TGF-beta 1. Overall, our findings demonstrate that a positive feedback mechanism exists within the canonical TGF-beta signaling pathway. This study also provides new insights into mechanism underlying the canonical TGF-beta signaling pathway, which regulates GC function and follicular development.

引用

页数：12

共 43 条

[21] Keratin 23, a novel DPC4/Smad4 target gene which binds 14-3-3ε [J].

Liffers, Sven-T ;

Maghnouj, Abdelouahid ;

Munding, Johanna B. ;

Jackstadt, Rene ;

Herbrand, Ulrike ;

Schulenborg, Thomas ;

Marcus, Katrin ;

Klein-Scory, Susanne ;

Schmiegel, Wolff ;

Schwarte-Waldhoff, Irmgard ;

Meyer, Helmut E. ;

Stuehler, Kai ;

Hahn, Stephan A. .

BMC CANCER, 2011, 11

[22] PPM1A functions as a Smad phosphatase to terminate TGFβ signaling (Publication with Expression of Concern. See vol. 166, 2016) (Publication with Expression of Concern. See vol. 165, pg. 498, 2016) [J].

Lin, Xia ;

Duan, Xueyan ;

Liang, Yao-Yun ;

Su, Ying ;

Wrighton, Katharine H. ;

Long, Jianyin ;

Hu, Min ;

Davis, Candi M. ;

Wang, Jinrong ;

Brunicardi, F. Charles ;

Shi, Yigong ;

Chen, Ye-Guang ;

Meng, Anming ;

Feng, Xin-Hua .

CELL, 2006, 125 (05) :915-928

[23] MicroRNA-26b Functions as a Proapoptotic Factor in Porcine Follicular Granulosa Cells by Targeting Sma-and Mad-Related Protein 4 [J].

Liu, Jiying ;

Du, Xing ;

Zhou, Jilong ;

Pan, Zengxiang ;

Liu, Honglin ;

Li, Qifa .

BIOLOGY OF REPRODUCTION, 2014, 91 (06)

[24] Comparative transcriptomic analysis reveals novel genes and regulatory mechanisms of Tetragenococcus halophilus in response to salt stress [J].

Liu, Licui ;

Si, Lifang ;

Meng, Xin ;

Luo, Lixin .

JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY, 2015, 42 (04) :601-616

[25] SUMO Modification Reverses Inhibitory Effects of Smad Nuclear Interacting Protein-1 in TGF-β Responses [J].

Liu, Sisi ;

Long, Jianyin ;

Yuan, Bo ;

Zheng, Mingjie ;

Xiao, Mu ;

Xu, Jianming ;

Lin, Xia ;

Feng, Xin-Hua .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (47) :24418-24430

[26] Tumor suppressor bromodomain-containing protein 7 cooperates with Smads to promote transforming growth factor-β responses [J].

Liu, T. ;

Zhao, M. ;

Liu, J. ;

He, Z. ;

Zhang, Y. ;

You, H. ;

Huang, J. ;

Lin, X. ;

Feng, X-H .

ONCOGENE, 2017, 36 (03) :362-372

[27] Mapping of chromosome 3p deletions in human epithelial ovarian tumors [J].

Lounis, H ;

Mes-Masson, AM ;

Dion, F ;

Bradley, WEC ;

Seymour, RJ ;

Provencher, D ;

Tonin, PN .

ONCOGENE, 1998, 17 (18) :2359-2365

[28] Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways [J].

Ma, Biao ;

Cheng, Hongcheng ;

Gao, Ruize ;

Mu, Chenglong ;

Chen, Ling ;

Wu, Shian ;

Chen, Quan ;

Zhu, Yushan .

NATURE COMMUNICATIONS, 2016, 7

[29] Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer [J].

Mishra, S. ;

Deng, J. J. ;

Gowda, P. S. ;

Rao, M. K. ;

Lin, C-L ;

Chen, C. L. ;

Huang, T. ;

Sun, L-Z .

ONCOGENE, 2014, 33 (31) :4097-4106

[30] Regulation of TGF-β Family Signaling by Inhibitory Smads [J].

Miyazawa, Keiji ;

Miyazono, Kohei .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2017, 9 (03)

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